tbuckley/cabot-search huggingface dataset:
Molecular Pathways and Mechanisms of TGFβ in Cancer Therapy
Authors: Mary Helen Barcellos-Hoff, James L. Gulley
Journal: Clinical Cancer Research (2023)

Abstract Even though the number of agents that inhibit TGFβ being tested in patients with cancer has grown substantially, clinical benefit from TGFβ inhibition has not yet been achieved. The myriad mechanisms in which TGFβ is protumorigenic may be a key obstacle to its effective deployment; cancer cells frequently employ TGFβ-regulated programs that engender plasticity, enable a permissive tumor microenvironment, and profoundly suppress immune recognition, which is the target of most current early-phase trials of TGFβ inhibitors. Here we discuss the implications of a less well-recognized aspect of TGFβ biology regulating DNA repair that mediates responses to radiation and chemotherapy. In cancers that are TGFβ signaling competent, TGFβ promotes effective DNA repair and suppresses error-prone repair, thus conferring resistance to genotoxic therapies and limiting tumor control. Cancers in which TGFβ signaling is intrinsically compromised are more responsive to standard genotoxic therapy. Recognition that TGFβ is a key moderator of both DNA repair and immunosuppression might be used to synergize combinations of genotoxic therapy and immunotherapy to benefit patients with cancer.
Genomic Patterns of Malignant Peripheral Nerve Sheath Tumor (MPNST) Evolution Correlate with Clinical Outcome and Are Detectable in Cell-Free DNA
Authors: Isidro Cortes-Ciriano, Christopher D. Steele, Katherine Piculell, Alyaa Al-Ibraheemi, Vanessa Eulo, Marilyn M. Bui, Aikaterini Chatzipli, Brendan C. Dickson, Dana C. Borcherding, Andrew Feber, Alon Galor, Jesse Hart, Kevin B. Jones, Justin T. Jordan, Raymond H. Kim, Daniel Lindsay, Colin Miller, Yoshihiro Nishida, Paula Z. Proszek, Jonathan Serrano, R. Taylor Sundby, Jeffrey J. Szymanski, Nicole J. Ullrich, David Viskochil, Xia Wang, Matija Snuderl, Peter J. Park, Adrienne M. Flanagan, Angela C. Hirbe, Nischalan Pillay, David T. Miller
Journal: Cancer Discovery (2023)

Abstract Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis. Significance: MPNST is the most common cause of death and morbidity for individuals with NF1, a relatively common tumor predisposition syndrome. Our results suggest that somatic copy-number and methylation profiling of tumor or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups. This article is highlighted in the In This Issue feature, p. 517
Maine Medical Center
Authors: David Ebenbach
Journal: JAMA (2023)

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Correction: Genetic Ancestry Inference from Cancer-Derived Molecular Data across Genomic and Transcriptomic Platforms
Authors: Pascal Belleau, Astrid Deschênes, Nyasha Chambwe, David A. Tuveson, Alexander Krasnitz
Journal: Cancer Research (2023)

In the earlier version of this article (1), as it was published online on November 9, 2022, a special case occurred for the estimation of the 95% confidence intervals for the accuracy and AUROC measure of performance where all the inferred ancestry calls agree with the ground truth. This special case could not be handled by the confidence interval estimation methods originally employed, and the corresponding entries were previously indicated as missing in Table 1. The authors subsequently adapted the estimation methods as necessary for handling this special case and provided the revised confidence interval estimates, which are reflected in Table 1 and Supplementary Tables S7, S8, S11, and S15–S18. The HTML and PDF versions of this article were corrected on December 13, 2022, ahead of print.
Volumetric imaging of optically cleared and fluorescently labeled animal tissue (VIOLA) for quantifying the 3D biodistribution of nanoparticles at cellular resolution in tumor tissue
Authors: Nikolai Rakhilin, Bing Yang, Mary E. Spilker, Lisa K. Manzuk, Mary Katherine Montgomery, Eyoung Shin, Nadira Prashad, Jungyeon Hwang, Youngho Song, Frank Loganzo, Anand Giddabasappa, Sripad Ram
Journal: Journal of Controlled Release (2023)
2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases
Authors: Anne R. Bass, Eliza Chakravarty, Elie A. Akl, Clifton O. Bingham, Leonard Calabrese, Laura C. Cappelli, Sindhu R. Johnson, Lisa F. Imundo, Kevin L. Winthrop, Reuben J. Arasaratnam, Lindsey R. Baden, Roberta Berard, S. Louis Bridges, Jonathan T. L. Cheah, Jeffrey R. Curtis, Polly J. Ferguson, Ida Hakkarinen, Karen B. Onel, Grayson Schultz, Vidya Sivaraman, Benjamin J. Smith, Jeffrey A. Sparks, Tiphanie P. Vogel, Eleanor Anderson Williams, Cassandra Calabrese, Joanne S. Cunha, Joann Fontanarosa, Miriah C. Gillispie‐Taylor, Elena Gkrouzman, Priyanka Iyer, Kimberly S. Lakin, Alexandra Legge, Mindy S. Lo, Megan M. Lockwood, Rebecca E. Sadun, Namrata Singh, Nancy Sullivan, Herman Tam, Marat Turgunbaev, Amy S. Turner, James Reston
Journal: Arthritis & Rheumatology (2023)

Objective To provide evidence‐based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs). Methods This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation. Results This guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence. Conclusion Application of these recommendations should consider patients’ individual risk for vaccine‐preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision‐making with patients is encouraged in clinical settings.
Biomarker signature and pathophysiological pathways in patients with chronic heart failure and metabolic syndrome
Authors: Camilla C.S. van der Hoef, Eva M. Boorsma, Johanna E. Emmens, Bart J. van Essen, Marco Metra, Leong L. Ng, Stefan D. Anker, Kenneth Dickstein, Ify R. Mordi, Adel Dihoum, Chim C. Lang, Dirk J. van Veldhuisen, Carolyn S.P. Lam, Adriaan A. Voors
Journal: European Journal of Heart Failure (2023)

The comorbidities that collectively define metabolic syndrome are common in patients with heart failure. However, the role of metabolic syndrome in the pathophysiology of heart failure is not well understood. We therefore investigated the clinical and biomarker correlates of metabolic syndrome in patients with heart failure.In 1103 patients with heart failure, we compared the biomarker expression using a panel of 363 biomarkers among patients with (n = 468 [42%]) and without (n = 635 [58%]) metabolic syndrome. Subsequently, a pathway overrepresentation analysis was performed to identify key biological pathways. Findings were validated in an independent cohort of 1433 patients with heart failure of whom 615 (43%) had metabolic syndrome. Metabolic syndrome was defined as the presence of three or more of five criteria, including central obesity, elevated serum triglycerides, reduced high-density lipoprotein cholesterol, insulin resistance and hypertension. The most significantly elevated biomarkers in patients with metabolic syndrome were leptin (log2 fold change 0.92, p = 5.85 × 10-21 ), fatty acid-binding protein 4 (log2 fold change 0.61, p = 1.21 × 10-11 ), interleukin-1 receptor antagonist (log2 fold change 0.47, p = 1.95 × 10-13 ), tumour necrosis factor receptor superfamily member 11a (log2 fold change 0.35, p = 4.16 × 10-9 ), and proto-oncogene tyrosine-protein kinase receptor Ret (log2 fold change 0.31, p = 4.87 × 10-9 ). Network analysis identified 10 pathways in the index cohort and 6 in the validation cohort, all related to inflammation. The primary overlapping pathway in both the index and validation cohorts was up-regulation of the natural killer cell-mediated cytotoxicity pathway.Metabolic syndrome is highly prevalent in heart failure and is associated with biomarkers and pathways relating to obesity, lipid metabolism and immune responses underlying chronic inflammation.
Global burden of primary liver cancer and its association with underlying aetiologies, sociodemographic status, and sex differences from 1990–2019: A DALY-based analysis of the Global Burden of Disease 2019 study
Authors: Sungchul Choi, Beom Kyung Kim, Dong Keon Yon, Seung Won Lee, Han Gyeol Lee, Ho Hyeok Chang, Seoyeon Park, Ai Koyanagi, Louis Jacob, Elena Dragioti, Joaquim Radua, Jae Il Shin, Seung Up Kim, Lee Smith
Journal: Clinical and Molecular Hepatology (2023)

Background/Aims: Global distribution of dominant liver cancer aetiologies has significantly changed over the past decades. This study analyzed the updated temporal trends of liver cancer aetiologies and sociodemographic status in 204 countries and territories from 1990 to 2019.Methods: The Global Burden of Disease 2019 report was used for statistical analysis. In addition, we performed stratification analysis to five quintiles using sociodemographic index and 21 geographic regions.Results: The crude numbers of liver cancer disease-adjusted life years (DALYs) and deaths significantly increased during the study period (DALYs; 11,278,630 in 1990 and 12,528,422 in 2019, deaths; 365,215 in 1990 and 484,577 in 2019). However, the Age-standardized DALY and mortality rates decreased. Hepatitis B virus (HBV) remains the leading cause of liver cancer DALYs and mortality, followed by hepatitis C virus (HCV), alcohol consumption, and non-alcoholic steatohepatitis/non-alcoholic fatty liver disease (NASH/NAFLD). Although Age-standardized DALY and mortality rates of liver cancer due to HBV and HCV have decreased, the rates due to alcohol consumption and NASH/NAFLD have increased. In 2019, the population of the East Asia region had the highest Age-standardized DALY and mortality rates, followed by high-income Asia-Pacific and Central Asia populations. Although East Asia and high-income Asia-Pacific regions showed a decrease during the study period, Age-standardized DALY rates increased in Central Asia. High-income North American and Australasian populations also showed a significant increase in Age-standardized DALY. Conclusions: Liver cancer remains an ongoing global threat. The burden of liver cancer associated with alcohol consumption and NASH/NAFLD is markedly increasing and projected to continuously increase.
Loss of <i>CDKN2A</i> Cooperates with <i>WWTR1(TAZ)–CAMTA1</i> Gene Fusion to Promote Tumor Progression in Epithelioid Hemangioendothelioma
Authors: Caleb N. Seavey, Andrea Hallett, Shuo Li, Kepeng Che, Ajaybabu V. Pobbati, Shuang Ma, Ashley Burtscher, Ryan Kanai, John M. Lamar, Brian P. Rubin
Journal: Clinical Cancer Research (2023)

Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma caused by the WWTR1(TAZ)-CAMTA1 (TC) gene fusion. This fusion gene has been observed in almost all reported EHE cases and functions as a constitutively activated TAZ. Sequencing of human tumors has, however, identified additional secondary mutations in approximately 50% of EHE, most commonly the loss of tumor suppressor CDKN2A. In this study, the effect of loss of CDKN2A in EHE tumorigenesis was evaluated.Mice bearing a conditional TC allele were paired with a conditional Cdkn2a knockout allele and an endothelial-specific Cre. Histologic characterization and single-cell RNA-seq of the resultant tumors were performed. EHE cell lines were established through ex vivo culture of tumor cells and evaluated for sensitivity to TEAD inhibition and trametinib.Loss of Cdkn2a within EHE was associated with more aggressive disease, as displayed by earlier tumor-related morbidity/mortality and enhanced tumor cell proliferation. As no previous EHE cell lines exist, we attempted, successfully, to expand EHE tumor cells ex vivo and produced the first EHE cell lines. These cell lines are "addicted" to the TC oncoprotein, replicate the EHE transcriptional profile, and generate EHE tumors when injected into immunodeficient mice.CDKN2A loss enhances the tumorigenicity of EHE in vivo and enabled the generation of the first cell lines of this disease. These cell lines replicate key facets of the human disease phenotype. Therefore, these cell lines and allograft tumors generated after implantation serve as robust model systems for therapeutic testing of compounds directed at either EHE or other TAZ-driven cancers.
Quantifying inflammation using interleukin‐6 for improved phenotyping and risk stratification in acute heart failure
Authors: Eleni Michou, Desiree Wussler, Maria Belkin, Cornelia Simmen, Ivo Strebel, Albina Nowak, Nikola Kozhuharov, Samyut Shrestha, Pedro Lopez‐Ayala, Zaid Sabti, Constantin Mork, Matthias Diebold, Tiffany Péquignot, Katharina Rentsch, Arnold von Eckardstein, Danielle M. Gualandro, Tobias Breidthardt, Christian Mueller
Journal: European Journal of Heart Failure (2023)
Mutation-associated transcripts reconstruct the prognostic features of oral tongue squamous cell carcinoma
Authors: Libo Liang, Yi Li, Binwu Ying, Xinyan Huang, Shenling Liao, Jiajin Yang, Ga Liao
Journal: International Journal of Oral Science (2023)

Abstract Tongue squamous cell carcinoma is highly malignant and has a poor prognosis. In this study, we aimed to combine whole-genome sequencing, whole-genome methylation, and whole-transcriptome analyses to understand the molecular mechanisms of tongue squamous cell carcinoma better. Oral tongue squamous cell carcinoma and adjacent normal tissues from five patients with tongue squamous cell carcinoma were included as five paired samples. After multi-omics sequencing, differentially methylated intervals, methylated loop sites, methylated promoters, and transcripts were screened for variation in all paired samples. Correlations were analyzed to determine biological processes in tongue squamous cell carcinoma. We found five mutated methylation promoters that were significantly associated with mRNA and lncRNA expression levels. Functional annotation of these transcripts revealed their involvement in triggering the mitogen-activated protein kinase cascade, which is associated with cancer progression and the development of drug resistance during treatment. The prognostic signature models constructed based on WDR81 and HNRNPH1 and combined clinical phenotype–gene prognostic signature models showed high predictive efficacy and can be applied to predict patient prognostic risk in clinical settings. We identified biological processes in tongue squamous cell carcinoma that are initiated by mutations in the methylation promoter and are associated with the expression levels of specific mRNAs and lncRNAs. Collectively, changes in transcript levels affect the prognosis of tongue squamous cell carcinoma patients.
Adipose tissue macrophages: implications for obesity-associated cancer
Authors: Bei Li, Si Sun, Juan-Juan Li, Jing-Ping Yuan, Sheng-Rong Sun, Qi Wu
Journal: Military Medical Research (2023)

Abstract Obesity is one of the most serious global health problems, with an incidence that increases yearly and coincides with the development of cancer. Adipose tissue macrophages (ATMs) are particularly important in this context and contribute to linking obesity-related inflammation and tumor progression. However, the functions of ATMs on the progression of obesity-associated cancer remain unclear. In this review, we describe the origins, phenotypes, and functions of ATMs. Subsequently, we summarize the potential mechanisms on the reprogramming of ATMs in the obesity-associated microenvironment, including the direct exchange of dysfunctional metabolites, inordinate cytokines and other signaling mediators, transfer of extracellular vesicle cargo, and variations in the gut microbiota and its metabolites. A better understanding of the properties and functions of ATMs under conditions of obesity will lead to the development of new therapeutic interventions for obesity-related cancer.
Real-life disease monitoring in follicular lymphoma patients using liquid biopsy ultra-deep sequencing and PET/CT
Authors: Ana Jiménez-Ubieto, María Poza, Alejandro Martin-Muñoz, Yanira Ruiz-Heredia, Sara Dorado, Gloria Figaredo, Juan Manuel Rosa-Rosa, Antonia Rodriguez, Carmen Barcena, Laura Parrilla Navamuel, Jaime Carrillo, Ricardo Sanchez, Laura Rufian, Alexandra Juárez, Margarita Rodriguez, Chongwu Wang, Paula de Toledo, Carlos Grande, Manuela Mollejo, Luis-Felipe Casado, María Calbacho, Tycho Baumann, Inmaculada Rapado, Miguel Gallardo, Pilar Sarandeses, Rosa Ayala, Joaquín Martínez-López, Santiago Barrio
Journal: Leukemia (2023)
Metabolomic Signatures Associated With Pulmonary Arterial Hypertension Outcomes
Authors: Hongyang Pi, Lu Xia, David D. Ralph, Samuel G. Rayner, Ali Shojaie, Peter J. Leary, Sina A. Gharib
Journal: Circulation Research (2023)

Background: Pulmonary arterial hypertension (PAH) is a complex disease characterized by progressive right ventricular (RV) failure leading to significant morbidity and mortality. Investigating metabolic features and pathways associated with RV dilation, mortality, and measures of disease severity can provide insight into molecular mechanisms, identify subphenotypes, and suggest potential therapeutic targets. Methods: We collected data from a prospective cohort of PAH participants and performed untargeted metabolomic profiling on 1045 metabolites from circulating blood. Analyses were intended to identify metabolomic differences across a range of common metrics in PAH (eg, dilated versus nondilated RV). Partial least squares discriminant analysis was first applied to assess the distinguishability of relevant outcomes. Significantly altered metabolites were then identified using linear regression, and Cox regression models (as appropriate for the specific outcome) with adjustments for age, sex, body mass index, and PAH cause. Models exploring RV maladaptation were further adjusted for pulmonary vascular resistance. Pathway enrichment analysis was performed to identify significantly dysregulated processes. Results: A total of 117 participants with PAH were included. Partial least squares discriminant analysis showed cluster differentiation between participants with dilated versus nondilated RVs, survivors versus nonsurvivors, and across a range of NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, REVEAL 2.0 composite scores, and 6-minute-walk distances. Polyamine and histidine pathways were associated with differences in RV dilation, mortality, NT-proBNP, REVEAL score, and 6-minute walk distance. Acylcarnitine pathways were associated with NT-proBNP, REVEAL score, and 6-minute walk distance. Sphingomyelin pathways were associated with RV dilation and NT-proBNP after adjustment for pulmonary vascular resistance. Conclusions: Distinct plasma metabolomic profiles are associated with RV dilation, mortality, and measures of disease severity in PAH. Polyamine, histidine, and sphingomyelin metabolic pathways represent promising candidates for identifying patients at high risk for poor outcomes and investigation into their roles as markers or mediators of disease progression and RV adaptation.
Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1 and XBB.1 by parental mRNA vaccine or a BA.5 bivalent booster
Authors: Chaitanya Kurhade, Jing Zou, Hongjie Xia, Mingru Liu, Hope C. Chang, Ping Ren, Xuping Xie, Pei‑Yong Shi
Journal: Nature Medicine (2022)
N‐terminal pro‐B‐type natriuretic peptide and h<scp>igh‐sensitivity</scp> troponin T hold diagnostic value in cardiac amyloidosis
Authors: Giuseppe Vergaro, Vincenzo Castiglione, Alberto Aimo, Concetta Prontera, Silvia Masotti, Veronica Musetti, Martin Nicol, Alain Cohen Solal, Damien Logeart, Georgios Georgiopoulos, Vladyslav Chubuchny, Alberto Giannoni, Aldo Clerico, Gabriele Buda, Kiara N. Patel, Yousuf Razvi, Rishi Patel, Ashutosh Wechalekar, Helen Lachmann, Philip N. Hawkins, Claudio Passino, Julian Gillmore, Michele Emdin, Marianna Fontana
Journal: European Journal of Heart Failure (2023)